Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease

The etiopathology of inflammatory bowel disease (IBD) remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflammation. IBD including Crohn's disease (CD) and ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Th1mediated inflammatory disorder while UC is regarded as a Th2like disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Th1 or Th2 cells, and several cytokines [e.g. interleukin (IL)-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Th1/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.     

Th17细胞及IL-23在炎症性肠病中的研究进展

炎症性肠病(IBD)是一种病因和发病机制尚不清楚的发生在胃肠道的慢性非特异性炎症性疾病。大量证据表明先天性和获得性免疫系统的异常均对该疾病起着关键性作用。传统观点认为炎症性肠病与Th1细胞和Th2细胞所介导的免疫应答有关;但最新研究指出,体内Th17细胞以及白细胞介素IL-23的存在,与炎症性肠病的发生息息相关。本文对炎症性肠病中Th17细胞及IL-23的研究进展作一综述。     

Special considerations for women with IBD

Inflammatory bowel diseases (IBD), namely Crohn disease (CD) and ulcerative colitis (UC), are common in Western society. Because at least half of the patients suffering from these diseases are women, it is important that physicians are aware of their gender-specific needs. There are multiple important concerns for women with UC and CD including issues of body image and sexuality, menstruation, contraception, screening for cervical cancer, matters related to menopause and hormone replacement therapy, osteoporosis, and the overlap seen between IBS and IBD. In this article, we have addressed these important, non-pregnancy-related issues faced by women with IBD.     

Extraintestinal manifestations in inflammatory bowel disease

Inflammatory bowel diseases (IBD) can be really considered to be systemic diseases since they are often associated with extraintestinal manifestations, complications, and other autoimmune disorders. Indeed, physicians who care for patients with ulcerative colitis and Crohn's disease, the two major forms of IBD, face a new clinical challenge every day, worsened by the very frequent rate of extraintestinal complications. The goal of this review is to provide an overview and an update on the extraintestinal complications occurring in IBD. Indeed, this paper highlights how virtually almost every organ system can be involved, principally eyes, skin, joints, kidneys, liver and biliary tracts, and vasculature (or vascular system) are the most common sites of systemic IBD and their involvement is dependent on different mechanisms.     

Inflammatory Bowel Disease in Auckland, New Zealand

Abstract: Inflammatory bowel disease in Auckland, New Zealand . R. J. Eason, S. P. Lee and C. Tasman–Jones, Aust. N.Z. J. Med., 1982, 12, pp. 125–131.
Four–hundred–and–fifty–six patients with ulcerative colitis (UC) and 137 patients with Crohn's disease (CD) attended public hospitals within Auckland between 1969 and 1978. Polynesians comprised 15% of the population at risk but accounted for only 0–4% of UC cases and no CD cases. Annual incidence rates were 5–4/100,000 Caucasians for UC and 1–75 for CD. CD was significantly less common in Auckland than in European and North American centres. For patients presenting for the first time between 1969 and 1978, the cumulative probability of surviving 10 years was 93–9% for UC and 89–1% for CD. An excess of observed over expected mortality was limited to the first year of observation in UC and did not occur in CD. Clinical features and local complications of UC and CD have been correlated with the anatomic location of disease. In this first clinical study of inflammatory bowel disease in New Zealand, 61% of CD and 23% of UC patients required at least one surgical resection.     

The IL-23/IL-17 pathway in inflammatory bowel disease

The etiology of inflammatory bowel disease is unknown but available evidence suggests that a deregulated immune response towards the commensal bacterial flora is responsible for intestinal inflammation in genetically predisposed individuals. IL-23 promotes expansion and maintenance of Th17 cells, which secrete the proinflammatory cytokine IL-17 and have been implicated in the pathogenesis of many chronic inflammatory disorders. Recent studies have shown that IL-23 also acts on cells of the innate immune system that can contribute to inflammatory cytokine production and tissue inflammation. A role for the IL-23/IL-17 pathway in the pathogenesis of chronic intestinal inflammation in inflammatory bowel disease has emerged from both animal and human studies. Here we aim to review the recent advances in this rapidly moving field.     

Association of Fas/Apo1 gene promoter (-670 A/G) polymorphism in Tunisian patients with IBD

AIM: To detect a possible association between the polymorphism of the (-670 A/G) Fas/Apo1 gene promoter and susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) in the Tunisian population. METHODS: The (-670 A/G) Fas polymorphism was analyzed in 105 patients with CD, 59 patients with UC, and 100 controls using the polymerase chain reaction restriction fragment length polymorphism method. RESULTS: Significantly lower frequencies of the Fas -670 A allele and A/A homozygous individuals were observed in CD and UC patients when compared with controls. Analysis of (-670 A/G) Fas polymorphism with respect to sex in CD and UC showed a significant difference in A/A genotypes between female patients and controls ( P corrected = 0.004 in CD patients and P corrected = 0.02 in UC patients, respectively). Analysis also showed a statistically significant association between genotype AA of the (-670 A/G) polymorphism and the ileum localization of the lesions ( P corrected = 0.048) and between genotype GG and the colon localization ( P corrected = 0.009). The analysis of inflammatory bowel disease patients according to clinical behavior revealed no difference. CONCLUSION: Fas-670 polymorphism was associated with the development of CD and UC in the Tunisian population.     

益生菌对炎症性肠病诱导缓解、维持治疗和贮袋炎作用系统评价

目的 评价益生菌对炎症性肠病缓解、维持治疗和贮袋炎的作用。方法 检索MEDLINE，EMBASE，the Cochrane Con—trolled Trials Register，OVID，BIOSIS和中国生物科技数据库，两位作者独立选取和炎症性肠病缓解率、复发率以及副作用相关的，对比益生菌治疗和非益生菌治疗的随机对照试验，使用Rev Man4．2．10软件统计分析，同时做亚组分析和敏感性分析。结果21项随机对照试验中共有1515例患者符合入选标准：4项研究评估了缓解率，14项研究评估了复发率，3项研究同时评估了缓解率和复发率。通过荟萃分析，炎症性肠病的总体缓解率相对危险度（relativerisk，RR）为1．05（95％CI=0．84—1．31），克罗恩病的缓解率RR0．85（95％CI=0．64—1．13），溃疡性结肠炎的缓解率RR1．18（95％CI=0．87—1．58）；贮袋炎临床复发率RR0．24（95％CI=0．12—0．48），克罗恩病临床复发率RR1．11（95％CI=0．69—1．80）；内镜复发率的RR1．08（95％CI=0．67—1．74）；益生菌与安慰剂比较，炎症性肠病的复发率RR0．51（95％CI=0．29—0．92）；益生菌与5-氨基水杨酸比较，溃疡性结肠炎的复发率RR0．96（95％CI=0．76—1．19）。结论 溃疡性结肠炎患者使用益生菌作为缓解治疗具有和5-氨基水杨酸相同的效果并优于安慰剂，但在炎症性肠病的诱导缓解中无额外益处。     

Inflammatory bowel disease in Tuzla Canton,Bosnia-Herzegovina: A prospective 10-year follow-up

BACKGROUNDThe incidence and prevalence of inflammatory bowel disease (IBD) vary between regions but have risen globally in recent decades. A lack of data from developing nations limits the understanding of IBD epidemiology.AIMTo perform a follow-up review of IBD epidemiology in the Tuzla Canton of Bosnia-Herzegovina during a 10-year period (2009-2019).METHODSWe prospectively evaluated the hospital records of both IBD inpatients and outpatients residing in Tuzla Canton for the specified period of time between January 1, 2009 and December 31, 2019. Since all our patients had undergone proximal and distal endoscopic evaluations at the hospital endoscopy unit, we used the hospital’s database as a primary data source, alongside an additional cross-relational search of the database. Both adult and pediatric patients were included in the study. Patients were grouped by IBD type, phenotype, age, and gender. Incidence rates were calculated with age standardization using the European standard population. Trends in incidence and prevalence were evaluated as a 3-year moving average and average annual percentage change rates.RESULTSDuring the 10-year follow-up period, 651 patients diagnosed with IBD were monitored (of whom 334, or 51.3%, were males, and 317, or 48.7%, were females). Of all the patients, 346 (53.1%) had been diagnosed with ulcerative colitis (UC), 292 (44.9%) with Crohn’s disease (CD), and 13 (2%) with indeterminate colitis (IC). We observed 440 newly diagnosed patients with IBD: 240 (54.5%) with UC, 190 (43.2%) with CD, and 10 (2.3%) with IC. The mean annual crude incidence rates were found to be 9.01/100000 population for IBD [95% confidence interval (CI): 8.17-9.85], with 4.91/100000 (95%CI: 4.29-5.54) for UC and 3.89/100000 (95%CI: 3.34-4.44) for CD. Calculated IBD prevalence in 2019 was 146.64/100000 (95%CI: 128.09-165.19), with 77.94/100000 (95%CI: 68.08-87.70) for UC and 65.77/100000 (95%CI: 54.45-74.1) for CD. The average annual IBD percentage change was 0.79% (95%CI: 0.60-0.88), with -2.82% (95%CI: -2.67 to -2.97) for UC and 6.92% (95%CI: 6.64-7.20) for CD. During the study period, 24,509 distal endoscopic procedures were performed. The incidence of IBD was 3.16/100 examinations (95%CI: 2.86-3.45) or 1.72/100 examinations (95%CI: 1.5-1.94) for UC and 1.36/100 examinations (95%CI: 1.17-1.56) for CD.CONCLUSIONTrends in the incidence and prevalence of IBD in Tuzla Canton are similar to Eastern European averages, although there are significant epidemiological differences within geographically close and demographically similar areas.     

Pharmacogenetics in inflammatory bowel disease

Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MIX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.     

未确定型结肠炎的特征分析

目的通过对未确定型结肠炎（indeterminate colitis，IC）患者的临床特点的分析，加深对该型结肠炎的认识。方法对2000年1月至2005年3月期间住院病历中符合炎症性肠病的217例患者的特点进行回顾性分析。结果未确定型结肠炎22例（10．2％），首发症状为腹泻54．5％，血便54．5％，腹痛31．8％，发热27．3％，有肠外表现59．1％，全结肠病变63．6％，回肠病变36．4％，节段型22．7％，直肠赦免50％，使用免疫抑制剂18．2％，手术31．8％。克罗恩病共60例，首发症状为腹痛76．7％，腹泻33．3％，发热25．0％，血便8．3％，有肠外表现38．3％，全结肠病变18．3％，节段型81．7％，回肠病变58．3％，使用免疫抑制剂11．7％，手术88．3％。溃疡性结肠炎135例，首发症状为脓血便78．5％，腹泻54．8％，腹痛29．6％，发热3．7％，有肠外表现18．5％，全结肠病变56．3％，节段型2．2％，回肠病变3．7％，使用免疫抑制剂的12．6％，手术6．7％。结论与克罗恩病及溃疡性结肠炎相比较，未确定型结肠炎有一些自己的特点，有可能是一个独立病变。     

Narrow-band imaging endoscopy to assess mucosal angiogenesis in inflammatory bowel disease: A pilot study

AIM: To investigate whether narrow band imaging (NBI) is a useful tool for the in vivo detection of angiogenesis in inflammatory bowel disease (IBD) patients. METHODS: Conventional and NBI colonoscopy was performed in 14 patients with colonic inflammation (8 ulcerative colitis and 6 Crohn’s disease). Biopsy samples were taken and CD31 expression was assayed immuno- histochemically; microvascular density was assessed by vessel count. RESULTS: In areas that were endoscopically normal but positive on NBI, ther...     

Treatment of inflammatory bowel disease： A review of medical therapy

Crohn＇s disease （CD） and ulcerative colitis （UC） are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor （TNF） alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non- systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine （6-MP） and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn＇s disease, and infliximab is also approved for the treatment of UC.     

炎症性肠病患者的肠外表现(附201例临床分析)

目的了解炎症性肠病(IBD)患者肠外表现的发生情况。方法对1978-01~2003-12期间北京大学第一医院收治的201例IBD患者的临床资料进行回顾性分析。结果25年间共收治IBD患者201例,其中溃疡性结肠炎(UC)患者182例,克罗恩病(CD)患者19例。IBD伴肠外表现发生率为20·9%(42/201),UC患者为21·43%(39/182),CD患者为15·79%(3/19)。女性显著多于男性(P<0·05)。UC患者年龄小于20岁者肠外表现发生率高(P<0·01),年龄大于50岁者肠外表现发生率低(P<0·01)。发生于UC活动期者占89·74%(35/39),而发生在缓解期者仅占10·26%(4/39);CD患者肠外表现均发生在活动期。肠外表现中关节、肌肉损害最为多见,其次为皮肤损害。侵犯泌尿系统、甲状腺及肝胆系统者罕见。伴有结节性红斑、坏疽性脓皮病及外周关节炎的患者多易合并其他种肠外表现。结论IBD患者伴有肠外表现者并非少见,女性年轻患者肠外表现发生率高,关节、肌肉及皮肤损害是IBD患者最多见的肠外表现,肠外表现的发生随IBD疾病活动性、疾病严重程度、病变范围的增加有增多的趋势。     

Pediatric inflammatory bowel disease

Inflammatory bowel disease is an important cause of gastrointestinal pathology in children and adolescents. The incidence of pediatric inflammatory bowel disease is increasing; therefore, it is important for the clinician to be aware of the presentation of this disease in the pediatric population. Laboratory tests, radiology studies, and endoscopic procedures are helpful in diagnosing inflammatory bowel disease and differentiating between Crohn's disease and ulcerative colitis. Once diagnosed, the goal of medical management is to induce remission of disease while minimizing the side effects of the medication. Specific attention needs to be paid to achieving normal growth in this susceptible population. Surgical management is usually indicated for failure of medical management, complication, or malignancy. Algorithms for diagnostic evaluation and treatment of pediatric inflammatory bowel disease are presented. The specific psychosocial issues facing these patients are also discussed in this review as are the future goals of research in the complex problem of pediatric inflammatory bowel disease.     

IBD5 polymorphisms in inflammatory bowel disease： Association with response to infliximab

AIM: Inflammatory bowel diseases (IBD) are multifactorial pathologies of unknown etiology. One susceptibility locus, IBD5, has been mapped to chromosome 5q31. We analyzed our Spanish cohorts of Crohn's disease (CD) and ulcerative colitis (DC) patients to determine whether this locus is associated with IBD, and to ascertain the main clinical phenotype influenced by this risk factor. The kind of interaction, either genetic heterogeneity or epistasis, between this IBD5 susceptibility region and the NOD2/CARD15 gene mutations was studied as well. Finally, we assessed whether this locus can predict response to infliximab therapy. METHODS: A case control study was performed with 274 CD and 211 UC patients recruited from a single center and 511 healthy ethnically matched controls. Two polymorphisms were genotyped in the IBD5 locus and three in the CARD15/NOD2 gene. RESULTS: Our results evidence association only with CD especially with the fistulizing phenotype and in the absence of NOD2/CARD15 variants (mutant allele frequency in patients vs controls: OR = 2.03, 95% CI = 1.35-3.06, P<0.01). The frequency of the IBD5 homozygous mutant genotype significantly increased in CD patients lacking response to infliximab (RR = 3.88, 95% CI = 1.18-12.0, P<0.05). UC patients overall do not show association with 5q31 polymorphisms, although a similar trend to the one observed in CD is found within the worse prognosis group. CONCLUSION: The IBD5 variants may enhance an individual carrier's risk for CD, mainly in the absence of the NOD2/CARD15 mutations and in fistulizing patients. The data presented suggest the potential role of the 5q31 polymorphisms as markers of response to infliximab.     

Adenosine： An immune modulator of inflammatory bowel diseases

Inflammatory bowel disease （IBD） is a common and lifelong disabling gastrointestinal disease. Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response. Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models. High extracellular adenosine suppresses and resolves chronic inflammation in IBD models. High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis. Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation. Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells, respectively. Increased extracellular adenosine levels activate the A2a receptor, which would reduce cytokines responsible for chronic inflammation.     

Thiopurine methyltransferase activity combined with 6-thioguanine metabolite levels predicts clinical response to thiopurines in patients with inflammatory bowel disease

BACKGROUND/AIMS: 6-Mercaptopurine and its prodrug azathioprine are effective for the treatment of inflammatory bowel disease. Thiopurine methyltransferase is important for the metabolism of thiopurines. However, there is controversy as to the clinical utility of measuring thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels. Our aim was to determine if thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide level monitoring would predict response to therapy with thiopurines in patients with inflammatory bowel disease. METHODS: Baseline thiopurine methyltransferase enzyme activity prior to initiation of therapy with either 6-mercaptopurine or azathioprine was determined in 39 patients with inflammatory bowel disease. The association between clinical response and thiopurine methyltransferase activity and 6-thioguanine nucleotide levels singly or in combination were analysed. RESULTS: Seventeen of 39 patients (44%) responded to 6-mercaptopurine or azathioprine therapy. Thiopurine methyltransferase enzyme activity below the mean of 30.5 U was significantly associated with clinical response. The thiopurine methyltransferase low phenotype was associated with response in 65% vs. 29% in individuals with thiopurine methyltransferase enzyme activity above 30.5 U (p = 0.05). There was no correlation between thiopurine methyltransferase activity and 6-thioguanine nucleotide levels. The maximal 6-thioguanine nucleotide levels did not predict clinical response. When combining thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels, the combination of thiopurine methyltransferase low/6-thioguanine nucleotide high was associated with response in 7/7 (100%) vs. only 2/8 (25%) with the combination of thiopurine methyltransferase high/6-thioguanine nucleotide low (p=0.01). CONCLUSIONS: Thiopurine methyltransferase activity inversely correlated with clinical response to thiopurine treatment in inflammatory bowel disease. Thiopurine methyltransferase enzyme activity below 30.5 U combined with a post-treatment 6-thioguanine nucleotide level > 230 pmol/8 x 10(8) erythrocytes was the best predictor of response.     

High incidence of inflammatory bowel disease in The Netherlands

PURPOSE: To gain recent epidemiologic information about inflammatory bowel disease in The Netherlands, a prospective study over four years (1991–1995) was performed. METHODS: The incidence of inflammatory bowel disease and its subgroups was examined using standardized reports of newly diagnosed patients. A separate study compared the Inflammatory Bowel Disease Registration and computerized diagnostic files of a subgroup of general practitioners with the aim of estimating completeness of case ascertainment. RESULTS: The following mean incidence rates (per 100,000 inhabitants and year) were found: 6.9 (95 percent confidence interval, 5.9–7.9) for Crohn's disease, 10 (95 percent confidence interval, 8.7–11.2) for ulcerative colitis (23 percent of these with ulcerative proctitis), and 1.1 (95 percent confidence interval, 0.7–1.5) for indeterminate colitis. In the age category 20 to 29 years, the incidence rate of Crohn's disease with small-bowel involvement was higher in females than in males. In extended ulcerative colitis, a male preponderance was observed in the older age groups. Estimated case ascertainment was 78 percent. CONCLUSIONS: Compared with recent studies in neighboring countries, the observed age and gender standardized incidence rates are high in the south of The Netherlands. Completeness of case ascertainment might have contributed to this observation; however, case ascertainment was low in ulcerative proctitis. In the study area, differences in age and gender standardized incidence rates and in disease localizations could be compatible with an influence of environmental risk factors.Supported by The Development Fund, University Hospital Maastricht, Byk BV, Zwanenburg, and Pharmacia BV, Woerden, The Netherlands. The European Collaborative Study of Inflammatory Bowel Disease has been assisted by a grant of the European Communities Brussels (DG XII-F-6).